There is a critical gap in evidence to guide recommendations to support or reject bariatric (weight loss) surgery (WLS) to treat severely obese adolescents with NASH. A prospective well-controlled study of the effectiveness of WLS vs. comprehensive lifestyle intervention (CLI) in treating NASH is urgently needed to guide recommendations, as severely obese adolescents are a large proportion of affected pediatric patients. Non-invasive tools to evaluate efficacy of treatment are also critically lacking. The lon-term goal is to identify highly effective treatment and non-invasive diagnostic biomarkers for NASH in children and adolescents given the rise in prevalence of pediatric obesity and NASH, and limited current therapy. The overall objective of this application is to assess the effectiveness of WLS vs. CLI as a treatment for NASH in severely obese adolescents. The central hypothesis is that WLS will result in significantly greater improvement in NASH in severely obese adolescents compared with CLI. This hypothesis derives from strong preliminary data generated by the applicants. The primary rationale for the proposed research is that, at completion, the study will provide critical evidence to guide treatment recommendations for severely obese adolescents with NASH. The central hypothesis will be tested by pursuing the following specific aims: 1) Evaluate the effectiveness of WLS vs. CLI in achieving significant histological improvement of NASH in severely obese adolescents; and 2) Test the sensitivity and specificity of novel non-invasive biomarkers in predicting histological outcome of NASH after treatment. Under the first aim, a prospective parallel cohort study of WLS vs. CLI will be conducted in adolescents, ages 13-19 with body mass index of 35-60 kg/m2. Primary histological outcomes will be measured after 1 year, controlling for important covariates that may impact weight loss and NASH outcomes. Well-established programs in NASH, adolescent WLS and multidisciplinary CLI exist at the performance site making this approach feasible in the applicants' hands. Under the second aim, measurements of serum cell death markers and innovative magnetic resonance measures of hepatic fat and fibrosis, supported by preliminary data generated by the applicants, will be combined to determine the correlation with histological NASH outcome at 1 year. The approach is innovative in: 1) focusing on severely obese adolescents with NASH, who are underrepresented in prior studies of CLI; 2) selecting a surgical approach, vertical sleeve gastrectomy, that has been linked to weight-loss independent beneficial effects on NASH pathogenesis; and 3) evaluating how emerging imaging methods and serological biomarkers can be used collectively and longitudinally to measure efficacy of treatment interventions on NASH. As the first controlled study of WLS vs. CLI in treatment of NASH, the proposed research is significant because it will fill a critical gap in evidence to guide patient and provider decision-making and may identify more effective treatments for NASH in severely obese adolescents. Cumulatively, this has the potential to yield dramatic improvements in medical and quality of life outcomes for a large proportion of pediatric patients with NASH, and reduce long term health care costs by ultimately decreasing progression to end-stage liver disease.